The present invention relates to the use of human embryonic stem cells to create blood-related cells, and the use of those blood-related cells for various purposes.
Techniques for isolating stable cultures of human embryonic stem cells have recently been described by our laboratory. See U.S. patent No. 5,843,780 and J. Thomson et al., 282 Science 1145-1147 (1998). The disclosure of these publications and of all other publications referred to herein are incorporated by reference as if fully set forth below.
We have deposited two of our human embryonic stem cell lines with the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209 U.S.A. on Jul. 7, 1999 and Jul. 15, 1999 respectively. Taxonomic descriptions of these deposits are human embryonic stem cell lines H1 and H9 respectively. It has been proposed in these publications that such cell lines may be used for, among other things, providing a source of specified cell lines of various types for research, transplantation and other purposes.
Under the storage and culturing conditions described in these publications the cell lines are maintained long term without differentiation into specific cell types. When the cell lines are subsequently injected into immunodeficient mice, they form teratomas demonstrating differentiation into multiple tissue types.
When ES cells are used to produce desired cells, it is often preferable to optimize differentiation towards specific cell types. In the case of hematopoietic cells it is desirable that this result in hematopoietic cells that can be isolated and used to form multiple hematopoietic lineages. These cells may include, but not be limited to, hematopoietic stem cells.
Hematopoietic stem cell populations have been isolated directly from bone marrow. See C. Baum et al. 89 PNAS USA 2804-2808 (1992). However, this relies on a supply of bone marrow to obtain the cells.
There have also been some attempts to direct murine embryonic cell populations towards hematopoietic cells. See e.g. U.S. Pat. No. 5,914,268; G. Keller, 7 Current Opinion In Cell Biology, 862-869 (1995); and T. Nakano et al. 265 Science 1098-1101 (1994). See also M. Weiss, 11 Aplastic Anemia And Stem Cell Biology, 1185-1195 (1997); and S. Morrison et al., 11 Annu. Rev. Cell Dev. Biol., 35-71 (1995).
However, applying these teachings to primates has proven difficult. For example, in F. Li et al., 92 Blood 368a (1998) there was a discussion of techniques for differentiation of rhesus embryonic stem cell lines using a stromal cell line and exogenous cytokines. However, that group has more recently reported that their techniques had inadequate formation of colonies.
The treatment of various diseases by tissue transplantation has become routine. However, there can be waiting lists to obtain natural donated organs, cells, or tissue. Even when the natural donor material becomes available there is often a problem with rejection. Traditional approaches for suppressing an immune response of recipients have drawbacks. For example, immunosuppressive drugs are costly and often have side effects.
In WO 98/07841 there was discussed techniques of deriving embryonic stem cells that are MHC compatible with a selected donor (e.g. transplanting a donor nucleus into an enucleated oocyte, followed by derivation of the stem cells therefrom). The application suggested that the resulting cells could be used to obtain MHC compatible hematopoietic stem cells for use in medical treatments requiring bone marrow transplantation.
However, some diseases such as type 1 diabetes mellitus or multiple sclerosis involve an autoimmune response. For example, merely transplanting pancreatic islets (which are MHC compatible to the diseased individual) to replace destroyed pancreatic islets will not provide sufficient long term reduction in type 1 diabetes mellitus, as the immune system of the host will still attack the transplanted islets.
It can therefore be seen that a need exists for techniques for causing human embryonic stem cell cultures to differentiate to desired hematopoietic colonies. Further, it is desired to develop improved uses for hematopoietic cells.